The acquisition of genomic alterations is a defining feature of human cancers. Cancer chemotherapy relies upon the cell death or apoptotic pathway to eradicate cells containing these alterations. The maintenance of appropriate methylation levels in DNA is necessary during normal DNA replication and mitosis. Disruption of correct and appropriate methylation leads to non-mutagenic changes associated with transcriptional silencing in tumor cells. Transcriptional silencing of genes along the apoptotic pathway abrogates the efficacy of chemotherapy and such tumors are refractory to classical therapy and associated with a poor prognosis. Epigenetic methylation of cytosine in DNA occurs at CpG sites in dense clusters of CpG dinucleotide repeats within gene promoters and is catalyzed by DNA methyl transferase enzymes (Dnmt's). Therapeutics that can inhibit Dnmt can reactivate genes silenced by hypermethylation, therefore, the design and development of novel Dnmt inhibitors is a worthy goal especially as the silenced genes remain intact and functional. We have constructed unique libraries of natural product derivatives based upon natural product isolation, combinatorial biosynthesis and parallel combinatorial synthesis. Our libraries are composed of structures that retain the topological and stereochemical complexity of natural products yet are straightforward to prepare. In screening our libraries against the human Dnmt-1 enzyme we discovered that compounds with an isoindolinone core scaffold were excellent inhibitors with Ki values as low as 20 micromolar. In this application we seek to demonstrate that we can develop potent and selective inhibitors of Dnmt-1. We further seek to demonstrate that our inhibitors cause reactivation of a model epigenetically silenced gene, human MLH1.